DESC:CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to and the benefit of Indian Patent Application No. 202321040698, filed on Jun. 15, 2023.

FIELD OF THE INVENTION
The present invention relates to a stable pharmaceutical composition of bempedoic acid and its combinations thereof and at least one pharmaceutically acceptable excipient and process for preparing thereof.

BACKGROUND OF THE INVENTION
Bempedoic acid, is an Adenosine Triphosphate-Citrate Lyase Inhibitor and it inhibits the synthesis of cholesterol in the liver, reducing low-density lipoprotein cholesterol (LDL-C) levels. Bempedoic acid, is an agent that lowers (LDL-C) by direct inhibition of hepatic adenosine triphosphate citrate lyase, leading to reduced de novo cholesterol synthesis and increased LDL receptor expression.
The drug substance used in the drug product formulation is the bempedoic acid is an alpha, omega-dicarboxylic acid that is pentadecanedioic acid which is substituted by methyl groups at positions 2 and 14, and by a hydroxy group at position 8, also known by the US accepted name of bempedoic acid (ETC-1002) and is chemically described as 8-hydroxy-2,2,14,14¬ tetramethyl-pentadecanedioic acid.
Its empirical formula is C19H36O5 and the molecular weight is 344.5 gm /mole and its structural formula is:

Bempedoic acid is a white to off-white crystalline powder that is highly soluble in ethanol, isopropanol and pH 8 phosphate buffer, and insoluble in water and aqueous solutions below pH 5. Bempedoic acid is a BCS class II compound i.e. poorly soluble in water and highly permeable.
Bempedoic acid is also available with the combination of Ezetimibe (cholesterol absorption inhibitor) for the treatment of as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.
Ezetimibe is an azetidinone derivative and a cholesterol absorption inhibitor with lipid-lowering activity. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of Ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.
The drug substance used in the drug product formulation is the beta-lactam that is azetidin-2-one also known by the US accepted name of Ezetimibe and is chemically described as 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)­hydroxypropyl]-4(S)-(4hydroxyphenyl)-2-azetidinone.
Its empirical formula is C24H21F2NO3 and the molecular weight is 409.4 gm /mole and its structural formula is:

Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe is a BCS class II compound i.e. poorly soluble in water and highly permeable.
Bempedoic acid is available in the United States of America as NEXLETOL® (bempedoic acid) tablet and is indicated for the treatment of as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. NEXLETOL® is available in one strength i.e. 180 mg and NEXLETOL® composition contains colloidal silicon dioxide, hydroxyl propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coating comprises of partially hydrolyzed polyvinyl alcohol, polyethylene glycol, talc, and titanium dioxide.
Bempedoic acid and Ezetimibe is available in the United States of America as NEXLIZET® (bempedoic acid and ezetimibe combination) tablet and is indicated for the treatment of as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. NEXLIZET® is available in one strength i.e. 180 mg; 10 mg and NEXLIZET® composition contains colloidal silicon dioxide, hydroxy propyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone K30, sodium lauryl sulfate, sodium starch glycolate. The film coating comprises of FD&C Blue #1/Brilliant Blue FCF Aluminum Lake, FD&C Blue #2/Indigo Carmine Aluminum Lake, glyceryl monocaprylocaprate, partially hydrolyzed polyvinyl alcohol, sodium lauryl sulfate, talc, and titanium dioxide.
USRE42461 patent discloses the compound of Ezetimibe or a pharmaceutically acceptable salt thereof.
US7335799 patent discloses the compound of bempedoic acid molecule or a pharmaceutically acceptable salt, hydrate, solvate or mixture thereof and also discloses the pharmaceutical composition comprising a compound and a pharmaceutically acceptable vehicle, excipient, or diluent which is administered in alone or in combination with second therapeutic agent or a statin.
US20220249380 patent application discloses a process for granulating bempedoic acid comprising dry mixing bempedoic acid, colloidal silicon dioxide and acceptable excipient to obtain dry mixture, separately mixing binder solution comprising hydroxypropyl cellulose (HPC-L) and colloidal silicon dioxide as binder solution and blending the dry mixture and binder solution to form a granulating blend and further discloses a process for manufacturing monolayer tablet comprising bempedoic acid granules and ezetimibe granules the process comprising dry mixing bempedoic acid, colloidal silicon dioxide to obtain dry mixture, granulation dry mixture with mixing binder solution comprising hydroxypropyl cellulose (HPC-L) and colloidal silicon dioxide to obtain bempedoic acid granules; and ezetimibe granules together to obtain granulated mixture and compressed into monolayer tablet.
IN202011045799 patent application discloses pharmaceutical composition comprising: a) intragranular portion comprising bempedoic acid or pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipient; and b) extragranular portion comprising one or more pharmaceutically acceptable excipient, wherein the intragranular portion is free of lubricant.
Bempedoic acid is a non-hygroscopic (negligible amount of moisture), exhibits sticky behaviour and poor flow characteristics. The observed stickiness and poor flow characteristics are process challenges to manufacturing steps of formulations including weighing, blending, granulation and compression.
Despite the aforementioned prior art solid pharmaceutical formulations of bempedoic acid requiring a glidant to reduce or ameliorate the problem of stickiness during the granulation process, there is still a need for alternate oral pharmaceutical compositions of bempedoic acid and/or combination of bempedoic acid and Ezetimibe capable of being stable, having desirable pharmacokinetics and improving the physiochemical properties of the composition parameters.
The present inventors have surprisingly found that the granulation of bempedoic acid made without the use of a glidant and manufactured by a process such as wet granulation exhibited excellent dissolution characteristics and was found to be stable and bioequivalent to the marketed formulation.

OBJECT OF THE INVENTION
The object of the present invention is to provide a stable pharmaceutical composition comprising a therapeutically effective amount of bempedoic acid, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another object of the present invention is to provide a stable pharmaceutical composition comprising a therapeutically effective amount of bempedoic acid, a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients, optionally with a second active ingredient.
It is also an object of the present invention to provide a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof;
b) one or more binders;
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is free of glidant.
It is another object of the present invention to provide a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof;
b) Ezetimibe or a pharmaceutically acceptable salt thereof;
c) one or more binders;
d) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is free of glidant.
It is also an object of the present invention to provide a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof;
b) one or more binders selected from the group consisting of hypromellose and co-povidone.
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is free of glidant.
It is another object of the present invention to provide a stable pharmaceutical composition for oral administration comprising:
a) about 50-54% w/w of Bempedoic acid;
b) about 1.5-3.0% w/w of copovidone;
c) one or more pharmaceutically acceptable excipients; and
wherein the said pharmaceutical composition is free of glidant.
It is also another object of the present invention to provide a stable pharmaceutical composition for oral administration comprising:
a) about 45-48% w/w of Bempedoic acid;
b) about 2.5-3.0% w/w of Ezetimibe;
c) about 1.5-2.5% w/w of hypromellose;
d) one or more pharmaceutically acceptable excipients, and
wherein the said pharmaceutical composition is free of glidant.
Yet another object of the present invention is to provide a solid, stable pharmaceutical composition comprising bempedoic acid or a pharmaceutically acceptable salt thereof, which uses a new and different beneficial formulation and is bioequivalent to the commercially available compositions in the United States of America, i.e. NEXLETOL® (bempedoic acid) tablets and/ or NEXLIZET® (bempedoic acid; Ezetimibe)

SUMMARY OF THE INVENTION
The present invention provides a stable pharmaceutical composition comprising a therapeutically effective amount of bempedoic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, optionally a second active ingredient.
In one aspect of the present invention, there is provided a stable pharmaceutical composition comprising a therapeutically effective amount of bempedoic acid, or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In another aspect of the present invention, there is provided a stable pharmaceutical composition comprising a therapeutically effective amount of bempedoic acid, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients optionally with a second active ingredient.
In another aspect of the present invention, there is provided a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof; b) one or more binders; c) one or more pharmaceutically acceptable excipients; and wherein the said, pharmaceutical composition is free of glidant.
In one another aspect of the present invention, there is provided a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof; b) one or more binders selected from the group consisting of hypromellose and copovidone; c) one or more pharmaceutically acceptable excipients; and wherein the said, pharmaceutical composition is free of glidant.
In one another aspect of the present invention, there is provided a stable pharmaceutical composition for oral administration comprising:
a) Bempedoic acid or a pharmaceutically acceptable salt thereof; b) Ezetimibe or a pharmaceutically acceptable salt thereof; c) one or more binders selected from the group consisting of hypromellose and copovidone; d) one or more pharmaceutically acceptable excipients; and wherein the said pharmaceutical composition is free of glidant.
In one another aspect of the present invention, there is provided a stable pharmaceutical composition for oral administration comprising:
a) about 50-54% w/w of Bempedoic acid; b) about 1.5-3.0% w/w of copovidone; c) one or more pharmaceutically acceptable excipients, and wherein the said pharmaceutical composition is free of glidant.
In another aspect of the present invention, there is provided a stable pharmaceutical composition for oral administration comprising:
a) about 45-48% w/w of Bempedoic acid; b) about 2.5-3.0% w/w of Ezetimibe; c) about 1.5-2.5% w/w of hypromellose; d) one or more pharmaceutically acceptable excipients, and
wherein the said pharmaceutical composition is free of glidant.
In one another aspect of the present invention, there is provided a process for the preparation of a stable pharmaceutical composition of bempedoic, acid and one or more pharmaceutically acceptable excipients comprising:
(i) Co-sift a bempedoic acid, microcrystalline cellulose, lactose monohydrate and sodium starch glycolate through an appropriate sieve and obtain a uniform blend, followed by the addition of sodium stearyl fumarate.
(ii) Load the bempedoic acid blend into a rapid mixer granulator.
(iii) Binder solution: Co-povidone was added into purified water with continuous stirring.
(iv) Granulating bempedoic acid blend using binder solution, dry the granules at a suitable temperature, and mill the granules with the appropriate screen.
(v) Lubrication: prepared granules are lubricated using magnesium stearate.
(vi) Compression & coating: compress the lubricated blend using suitable punches and coat the core tablet using Opadry II white dispersion.
In one another aspect of the present invention, there is provided a process for the preparation of a stable pharmaceutical composition of bempedoic acid and Ezetimibe, and one or more pharmaceutically acceptable excipients, comprising:
A. Bempedoic acid granules:
(i) Co-sift a bempedoic acid, microcrystalline cellulose, lactose monohydrate and sodium stearyl fumarate;
(ii) Load the bempedoic acid blend into a rapid mixer granulator;
(iii) Binder solution: hypromellose was added into purified water with continuous stirring;
(iv) Granulating bempedoic acid blend using binder solution, dry the granules at a suitable temperature, and mill the granules with an appropriate screen;
B. Ezetimibe granules:
(i) Co-sift Ezetimibe, lactose monohydrate, and microcrystalline cellulose in a fluid bed processor;
(ii) Binder solution: hypromellose dissolved in purified water;
(iii) A binder solution was used for granulating the ezetimibe blend using the top spray granulation method and drying the granules at a suitable temperature;
C. Milling and blending:
(i) dried granules of bempedoic acid and Ezetimibe and added sodium starch glycolate and lactose monohydrate were milled;
(ii) Lubrication: prepared granules were lubricated using magnesium stearate;
(iii) Compression & coating: compress the lubricated blend using suitable punches and coat the core tablet using Opadry II blue dispersion;

DETAILED DESCRIPTION OF THE INVENTION
Before the present process and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is not intended to be limiting since the scope of the present invention will be limited only by the appended claims. It is also to be understood that the terminology used herein only describes particular embodiments.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more steps and equivalents thereof known to those skilled in the art, and so forth.
The publications discussed herein are provided solely for their availability to the applicant prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed
The term "stable", as used herein means the tablet composition, when subjected to stability conditions of 40ºC and 75% RH and 25°C/ 60% RH for a period of one months, three months and six months produces total impurities of NMT 2%. Pharmaceutical compositions of the present invention comprising bempedoic acid and their combination are found to be stable.
The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amount, if indicated), as well as any product which results, directly or indirectly, from a combination of the specified ingredients in the specified amounts. Further, the term "composition" or "formulation", or "dosage form" as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets (e.g. bilayer or trilayer), beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration. By "pharmaceutically acceptable", it means that the diluent, excipient or carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term "pharmaceutically acceptable" as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of animals, in particular human beings, without excessive toxicity, irritation, allergic response, or other problematic complications commensurate with a reasonable benefit/risk ratio.
The term "coating" as used herein, refers to adherence, and/or adsorption, preferable uniformly, of at least one solution, dispersion or suspension coating material onto a substrate. The coating material on the substrate may be of any thickness. Preferably the coating material is a thin and uniform film applied onto the substrate. A thin and uniform film can be of the type of a "film coating" or/and an "isolating film coating" or/and an "external film coating".
The term "therapeutically effective amount" is defined to mean the amount or quantity of the active drug bempedoic acid and Ezetimibe, which is sufficient to elicit an appreciable biological response when administered to the patient. A person skilled in the art can easily determine such an amount by routine experimentation and with an undue burden. A therapeutically effective amount of bempedoic acid and bempedoic acid combination with Ezetimibe is present in the formulation of the invention in a weight ratio of about 18:1 of bempedoic acid to Ezetimibe, and the respect of this invention is usually bempedoic acid 180mg and bempedoic acid and ezetimibe 180mg /10mg, usually administered orally once daily of administration are feasible for use in therapy under prescribed medical conditions. As mentioned, dosage forms of the present invention are useful, inter alia, in treating the subject's heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease requiring additional lowering of LDL-C.
In accordance with the present invention, the "bempedoic acid", unless indicated otherwise in the specification, refers to bempedoic acid in the form of a free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably bempedoic acid is in the form of bempedoic acid-free base and a different crystalline form of bempedoic acid used in the present invention.
In accordance with the present invention, the "ezetimibe" unless indicated otherwise in the specification, refers to Ezetimibe in the form of a free base or its pharmaceutically acceptable salt, amorphous, crystalline or any isomer or derivative, hydrate or solvate, prodrug or combinations thereof. Preferably Ezetimibe is in the form of Ezetimibe free base and further crystalline form X of Ezetimibe used in the present invention.
An important aspect of the present invention provides compositions of bempedoic acid and Ezetimibe or a pharmaceutically acceptable salt thereof that are stable. The concentration of bempedoic acid, or a pharmaceutically acceptable salt thereof, used in the pharmaceutical composition ranges from 35% w/w to 60% w/w by weight of the pharmaceutical composition. The concentration of Ezetimibe, or a pharmaceutically acceptable salt thereof, used in the pharmaceutical composition ranges from 1% w/w to 5% w/w by weight of the pharmaceutical composition. It is required that compositions comprising bempedoic acid and Ezetimibe as an activity are chemically stable as degradation by oxidation, hydrolysis, isomerization, photolysis, polymerization, or any other method of degradation, could lead to a change in bioavailability and could also lead to toxicity. Chemical stability can be measured by a suitable, stability-indicating chromatographic method for determining degradation products.
Another important aspect of the present invention is that it provides a stable pharmaceutical composition comprising bempedoic acid and their combination thereof prepared by a wet granulation process, compression and film coating.
In yet another embodiment, the present invention provides stable pharmaceutical compositions comprising bempedoic acid as a first active agent, optionally a second active agent(s), and optionally one or more other pharmaceutically acceptable excipients (s). The second active agent(s) that can be used in the present invention include, but not limited to, statin (lovastatin, simvastatin, rosuvastatin, atorvastatin, fluvastatin, pravastatin); a thiazolidinedione or fibrate; a bile-acid-binding-resin; a niacin; an anti-obesity drug; a hormone; a tyrophostine; a sulfonylurea-based drug; a biguanide; an a-glucosidase inhibitor; cholesterol absorption inhibitor; a cardiovascular drug; an HDL-raising drug; an HDL enhancer; or a pharmaceutically acceptable salt thereof. In an embodiment of the present invention, the preferred second active agent is an ezetimibe.
Film coats may be prepared from ready-to-make preparations which are available on the market. One preferred film-coat material is OPADRY®, particularly OPADRY®white (hydrolyzed polyvinyl alcohol-part, titanium dioxide, macrogol/polyethylene glycol and talc) OPADRY® AMB blue (hydrolyzed polyvinyl alcohol-part, titanium dioxide, FD&C blue /indigo carmine aluminium lake, glycerol, sodium lauryl sulfate and FD&C blue /brilliant blue FCF aluminium lake and talc). A film coating dispersion or suspension can be prepared by using different solvents (water, alcohols, ketones, esters, chlorinated hydrocarbons), but water is preferred.
The application of a specified compression force to prepare the dosage forms of the present invention is another important aspect of the present invention. Applying the specified compression force to the granules or the blend prepared according to the present invention results in dosage forms having desired dissolution and stability profile. The compression force is applied by an upper and lower punch to carry out the compression step. The compression force (N) applied during the compression step of the process of the present invention is in the range of from 50 to 300 N, preferably from 50 to 200 N, more preferably from 50 to 150 N. In another embodiment of the present invention, stable pharmaceutical compositions of bempedoic acid and bempedoic acid combination with Ezetimibe or a pharmaceutically acceptable salt thereof of the present invention show desired dissolution characteristics.
The composition(s), according to the present invention, when tested for in- vitro dissolution profile, exhibits dissolution such that the amount of the drug equivalent to 95 to 100% dissolves within 30 minutes. To study the dissolution criterion, the suitable dissolution test is selected and it is carried out in an aqueous media non-buffered or buffered to a pH range (1 to 7.8) found in the gastrointestinal tract and controlled at 37°C (± l0°C), that maintain a physiological relevance. Various dosages, such as tablets, capsules can be studied for dissolution profile, in a standard prescribed manner. When the dosage form is a tablet, typically paddles rotating at 50-75 rpm are used to test the dissolution rate of the tablets. The amount of dissolved active can be determined using suitable analytical techniques such as UV or HPLC.
Since in-vivo-in-vitro relationships are established, the dissolution (in-vitro) test, in addition to its application as a quality control technique, can more preferably be used to predict the tablet's biological (in-vivo) performance. In one of the embodiments, the dissolution test is performed in 900 mL of dissolution medium at 37° C., using USP Apparatus 2 (paddles) method at a rotation speed of 50 rpm. Samples are removed after 5, 10, 15, 20, 30, 45, and 60 minutes from test initiation and analyzed for bempedoic acid and their combinations. Phosphate buffer, pH 6.6 deaerated solution has been used as dissolution medium.
The term "excipient" as used herein means a pharmacologically inactive component such as, but not limited to, a diluent or filler, binder, solvent, disintegrant, lubricant, surfactant, colourant or the like. The excipients useful in preparing a pharmaceutical composition are generally safe, non-toxic and acceptable for human use. Reference to an excipient includes one and more than one such excipient, and the excipients may be added intragranularly or extragranularly.
"Fillers or diluents" may be selected from, but not limited to, carbohydrates, confectioners' sugar, compressible sugars, dextrose, dextrin, fructose, lactitol, xylitol, sorbitol, microcrystalline cellulose, mannitol, lactose, lactose monohydrate, sucrose, maltose, starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, or combinations thereof. In an embodiment of the present invention, preferred diluents or fillers are microcrystalline cellulose and lactose monohydrate. The fillers or diluents may be used in the range of about 0.5% w/w to about 50% w/w, preferably about 1% w/w to about 40% w/w, more preferably about 1% w/w to about 35% w/w of the total weight of stable oral pharmaceutical composition. The preferred filler or diluent is lactose monohydrate, microcrystalline cellulose or combinations thereof.
"Binders" may be selected from, but not limited to, potato starch, wheat starch, com starch, microcrystalline cellulose, celluloses such as hydroxy propyl cellulose, hydroxy propyl methylcellulose (hypromellose), povidone, co-povidone, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, natural gums like acacia, alginic acid, guar gum, liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, or combinations thereof. In an embodiment of the present invention, preferred binders are hydroxy propyl methylcellulose and co-povidone. The binders may be used in the range of about 0.1% w/w to about 20% w/w, preferably about 0.5% w/w to about 15% w/w, more preferably about 0.5% w/w to about 10% w/w of the total weight of stable oral pharmaceutical composition. The preferred binder Hypromellose or co-povidone or combinations thereof.
"Granulating solvent" used in the present invention includes, but is not limited to, anhydrous, hydrous, or a mixture thereof. Suitable anhydrous and hydrous solvents include, but not limited to, water, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, toluene, tetrachloroethylene, methyl acetate, ethyl acetate, hexane, benzene, tetrahydrofuran, chloroform, methylene chloride, or mixtures thereof. In the embodiment of the present invention, purified water is preferred as a hydrous solvent.
"Disintegrants" may be selected from, but not limited to, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate, starches or combinations thereof. In an embodiment of the present invention, preferred disintegrants are sodium starch glycolate and croscarmellose sodium. The disintegrants may be used in the range of about 0.5% w/w to about 25% w/w, preferably about 0.7% w/w to about 20% w/w, more preferably about 1% w/w to about 18% w/w of the total weight of stable oral pharmaceutical composition.
"Lubricants" may be selected from, but not limited to, aluminium stearate, zinc stearate, calcium stearate, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, mineral oil, hydrogenated vegetable oil, stearic acid, magnesium aluminum silicate, sodium stearyl fumarate, glyceryl behenate, sodium benzoate or mixtures thereof. In an embodiment of the present invention, preferred lubricants are sodium stearyl fumarate and magnesium stearate. The lubricants may be used in the range of about 0.1% w/w to about 20% w/w, preferably about 0.5% w/w to about 15% w/w, more preferably about 0.5% w/w to about 10% w/w of the total weight of stable oral pharmaceutical composition.
"Surfactants" or solubilize are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. The surfactants can be selected from, but not limited to, hydrophilic surfactants or lipophilic surfactants or mixtures thereof. Surfactants according to the present invention are selected from, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol (PEG) fatty acid esters such as PEG monolaurate, PEG dilaurate, PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate and the like, used either alone or in combination thereof. In an embodiment of the present invention, preferred surfactant is sodium lauryl sulphate. The surfactants may be used in the range of 0.01% w/w to about 10% w/w, preferably in the range of 0.1% w/w to about 7% w/w, more preferably in the range of 0.5% w/w to 5% w/w of the total weight of stable oral pharmaceutical composition.
The compositions in accordance with the present invention can be prepared either by direct compression, dry granulation like slugging or roller compaction, or by wet granulation. With respect to the present invention, the wet granulation method may comprise use of non- aqueous organic solvent(s) such as dichloromethane, ethanol, acetone, methylene chloride and the like, or a mixture thereof, as the granulating aid.
The compositions in accordance with the present invention can also be prepared using a granulation method, which may comprise use of an anhydrous solvent(s), hydrous solvent(s) or mixture thereof as granulating solvent(s).
The pharmaceutical compositions of the present invention may be further coated with a functional or nonfunctional coating. The coating composition may be comprised of pharmaceutically acceptable excipients such as coating agents, binders, plasticizers, coloring agents, and opacifiers. The total weight gain after coating may be about 1% w/w to 10% w/w of the uncoated pharmaceutical composition.
In yet another embodiment, the stable pharmaceutical composition is optionally coated with about 1% w/w to about 5% w/w of Opadry AMB blue and opadry II white based on the total weight of the composition.
"Coating agents" which are useful in coating process, may be selected from, but not limited to, water soluble polymers such as, but not limited to, polyvinylpyrrolidone or water soluble cellulose such as, but not limited to, hydroxy propyl methyl cellulose or hydroxy propyl cellulose. It may be selected from, but not limited to, soluble agents such as polysorbate 80, polysaccharides such as maltodextrin, acacia, com, sucrose, gelatin, shellac, cellulose acetate phthalate, lipids, synthetic resins, acrylic polymers, opadry, polyvinyl alcohol, copolymers of vinyl pyrrolidone, vinyl acetate or combinations thereof. These may be applied from aqueous or non-aqueous systems or combinations of aqueous and non-aqueous systems as appropriate.
Examples of binders for coating include cellulose or cellulose derivatives such as, but not limited to, methylcellulose, HPMC, hydroxypropyl cellulose, and carboxymethyl cellulose sodium, and microcrystalline cellulose, alginic acid, sodium alginate and gelatin, polyvinyl pyrrolidone, copovidone, starch, pregelatinized starch, or mixtures thereof. Examples of plasticizers for coating include, but are not limited to, propylene glycol, triethyl citrate, tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol, diethyl phthalate, acetylated monoglycerides, or mixtures thereof. Examples of opacifiers for coating include, but not limited to, titanium dioxide, calcium carbonate, behenic acid, cetyl alcohol, or mixtures thereof. Examples of coloring agents for coating include, but not limited to, FDA approved colorants such as iron oxide, lake of tartrazine, allura red, lake of quinoline yellow, lake of erythrosine, titanium dioxide, or mixtures thereof. Suitable solvents for the coating include, but not limited to, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone, or mixtures thereof.
Another aspect of the present invention provides the compositions comprising bempedoic acid and their combination packed or stored into the bottle, blister pack, pouch, or any corresponding packing known to a person skilled in the art in which the dosage form or the pharmaceutical compositions are packed or stored. In an embodiment of the present invention, bempedoic acid and their combination compositions are packed or stored into the bottle, blister pack, or pouch comprising a desiccant. The term "desiccant" is referred herein to a substance used to remove or suppress or decrease the odour or to absorb moisture which prevents degradation and/or decomposition of the active agent(s). The desiccant may be placed in the internal space of the package containing the composition, in an amount sufficient to remove the odorous material or to suppress or reduce the smell. In one embodiment, the desiccants are selected from, but not limited to, a synthetic zeolite, silica gel, silica-alumina, an active carbon, metallic oxide such as calcium oxide and the like used either alone or in combinations thereof.
An aspect of the present invention provides a method of using the compositions of the present invention comprising bempedoic acid or a pharmaceutically acceptable salt thereof for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Another aspect of the present invention further provides a method of using the compositions of the present invention comprising a therapeutically effective amount of bempedoic acid or a pharmaceutically acceptable salt thereof and optionally second active agent for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. It should be appreciated that the invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete and will convey the scope of the invention to those skilled in the art. Other features and embodiments of the invention will become apparent from the following examples, which are given for illustration of the invention rather than for limiting its intended scope.
In one embodiment, the invention comprises a stable pharmaceutical composition for oral administration comprising a) bempedoic acid or a pharmaceutically acceptable salt thereof; b) binder; c) diluent; d) disintegrant; e) lubricant; f) coating material; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the invention comprises a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises a) about 40-55% of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 15-18% of microcrystalline cellulose; c) about 2-4 % Co-povidone; d) about 07-09% of lactose monohydrate; e) about 10-12% of sodium starch glycolate; f) about 1.0-1.5% of magnesium stearate; g) about 0.5-1.0% of sodium stearyl fumarate; h) about 2.0-3.0% of Opadry II White; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the invention comprises a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises a) about 45-60% w/w of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 10-25% w/w of microcrystalline cellulose; c) about 1-4% w/w of % Co-povidone; d) about 5-12% w/w of lactose monohydrate; e) about 5-12% w/w of sodium starch glycolate; f) about 0.2-4% w/w of magnesium stearate; g) about 0.1-3% of sodium stearyl fumarate; h) about 1-4% w/w of Opadry II White; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the invention comprises a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises a) about 54% w/w of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 1% w/w of sodium stearyl fumarate; c) about 18% w/w of microcrystalline cellulose; d) about 9% w/w of lactose monohydrate; e) about 11.5% w/w of sodium starch glycolate, f) about 3% w/w of co-povidone, g) about 1.3% w/w of magnesium stearate, h) about 2.7% w/w of opadry white film coating based on total weight of the composition; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the invention comprises a stable pharmaceutical composition in a tablet dosage form wherein the tablet comprises a) about 180 mg of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 60 mg of microcrystalline cellulose; c) about 10 mg of Co-povidone; d) about 30 mg of lactose monohydrate; e) about 38.4 mg of sodium starch glycolate; f) about 4.1 mg of magnesium stearate; g) about 3.3 mg of sodium stearyl fumarate;h) about 9 mg of Opadry II White; based on total weight of the composition; and wherein the pharmaceutical composition is free of glidant
In yet another embodiment, the invention comprises a stable pharmaceutical composition for oral administration comprising a) bempedoic acid or a pharmaceutically acceptable salt thereof; b) ezetimibe or a pharmaceutically acceptable salt thereof; c) binder; d)diluent; e) disintegrant; f) lubricant; g) surfactant; h) coating material; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the present invention comprises a stable pharmaceutical composition in a monolayer tablet dosage form wherein the tablet comprises a) about 44-55% of bempedoic acid or a pharmaceutically acceptable salt thereof;b) about 2.5-3.0% of Ezetimibe or a pharmaceutically acceptable salt thereof; c) about 1.5-2.5% of hypromellose; d) about 10-15% of microcrystalline cellulose; e) about 20-24% of lactose monohydrate; f) about 3.5-4.5% of sodium starch glycolate; g) about 0.5-1.1% of croscarmellose sodium; h) about 0.5-1.1% of magnesium stearate; i) about 0.1-0.7% of sodium stearyl fumarate; j) about 0.45-0.60% of sodium lauryl sulfate; k) about 2.0-2.5% of Opadry AMB blue; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the present invention comprises a stable pharmaceutical composition in a monolayer tablet dosage form wherein the tablet comprises: a) about 180 mg of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 10 mg of ezetimibe or a pharmaceutically acceptable salt thereof; c) about 9 mg of hypromellose; d) about 53 mg of microcrystalline cellulose; e) about 85.5 mg of lactose monohydrate; f) about 17 mg of sodium starch glycolate; g) about 4 mg of croscarmellose sodium; h) about 4 mg of magnesium stearate; i) about 2.5 mg of sodium stearyl fumarate; j) about 2.2 mg of sodium lauryl sulfate; k) about 9 mg of Opadry AMB blue ; and wherein the pharmaceutical composition is free of glidant.
In another embodiment, the present invention comprises a stable pharmaceutical composition in a monolayer tablet dosage form wherein the tablet comprises: a) Ezetimibe part comprising about 1-5% w/w of ezetimibe, 15-25% w/w of lactose monohydrate, about 0.5-3% w/w of sodium starch glycolate, about 2-10% w/w of microcrystalline cellulose, about 0.1-2% w/w of hypromellose, about 0.1-2% w/w of sodium lauryl sulfate; b) Bempedoic acid part comprising about 35-55% w/w of bempedoic acid, about 2-8% w/w of microcrystalline cellulose, about 0.1-2% w/w of sodium stearyl fumarate, about 1-7% w/w of lactose monohydrate, 0.5-3% w/w of Hypromellose; c) Extragranular part comprising about 1-5% w/w of sodium starch glycolate, about 0.5-4% w/w of lactose monohydrate, about 1-5% w/w of microcrystalline cellulose, about 0.1-3% w/w of croscarmellose sodium, about 0.1-3% w/w of magnesium stearate and film coating comprising about 1-5% w/w of opadry AMB blue; wherein the pharmaceutical composition is free of glidant.
In another embodiment, the present invention comprises a stable pharmaceutical composition in a monolayer tablet dosage form wherein the tablet comprises: a) Ezetimibe part comprising about 2.7% w/w of ezetimibe, 18% w/w of lactose monohydrate, about 1.6% w/w of sodium starch glycolate, about 6.1% w/w of microcrystalline cellulose, about 0.6% w/w of Hypromellose, about 0.6% w/w of sodium lauryl sulfate; b) Bempedoic acid part comprising about 48% w/w of bempedoic acid, about 5% w/w of microcrystalline cellulose, about 0.7% w/w of sodium stearyl fumarate, about 4% w/w of lactose monohydrate, 2% w/w of Hypromellose; c) Extragranular part comprising about 3% w/w of sodium starch glycolate, about 1% w/w of lactose monohydrate, about 3.2 % w/w of microcrystalline cellulose, about 1% w/w of croscarmellose sodium, about 1% w/w of magnesium stearate and film coating comprising about 2.4% w/w of opadry AMB blue, and wherein the pharmaceutical composition is free of glidant.
Additionally, N-nitrosamine impurities are possible in the synthesis of Bempedoic acid and/or ezetimibe and its pharmaceutical salt thereof. The N-nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of N-nitrosamine impurities include, but are not limited to, N-Nitroso Bempedoic acid, N-Nitroso ezetimibe, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). N-nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the N-nitrosamine impurities in drugs is generally low, some levels have been above the US Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of N-nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for N-nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
The pharmaceutical compositions of the present invention may be prepared by conventional processes such as wet granulation, dry granulation or direct compression as known to those skilled in the art.
An aspect of the present invention relates to a tablet composition of Bempedoic acid, wherein said tablet is bioequivalent to the marketed Bempedoic acid tablets sold under the brand name, NEXLETOL®.
In another aspect of the present invention relates to a tablet composition comprising a combination of Bempedoic acid and Ezetimibe, wherein said tablet is bioequivalent to the marketed combination of Bempedoic acid and Ezetimibe tablets sold under the brand name, NEXLIZET®.
Bioequivalence is established by comparing the pharmacokinetic parameters, for example AUC and Cmax, of the tablet composition of the present invention with NEXLETOL® tablets in healthy human subjects. Bioequivalence is established by comparing pharmacokinetic parameters, for example AUC and Cmax, of the tablet composition of the present invention with NEXLIZET® tablets in healthy human subjects.
The term “AUC” refers to the area under the time/plasma concentration curve following administration of a bempedoic acid and/or ezetimibe pharmaceutical composition.
The term “Cmax” refers to the maximum concentration of bempedoic acid and/or ezetimibe in the blood following the administration of a bempedoic acid and/or ezetimibe pharmaceutical composition.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example 1
Table-1
Sr. No. Ingredients Amount
(mg/tablet)
Dry Mix:
1 Bempedoic acid 180.0
2 Sodium stearyl fumarate 3.30
3 Microcrystalline cellulose 30.0
4 Lactose monohydrate 30.0
5 Sodium Starch Glycolate 13.0
Binder
6 Co-povidone 10.0
7 Purified Water @ q.s
Pre-lubrication
8 Microcrystalline cellulose 29.2
9 Sodium starch glycolate 25.4
Lubrication:
10 Magnesium Stearate 4.1
Core tablet weight 325.00
Film Coating:
11 Opadry II White 9.0
12 Purified Water q.s.
Coated tablet weight 334.00

Manufacturing procedure:
(i) Co-sift a bempedoic acid, microcrystalline cellulose, lactose monohydrate and sodium starch glycolate through an appropriate sieve and obtain a uniform blend, followed by the addition of sodium stearyl fumarate.
(ii) Load the bempedoic acid blend into a rapid mixer granulator.
(iii) Binder solution: Co-povidone was added into purified water with continuous stirring.
(iv) Granulating bempedoic acid blend using binder solution, dry the granules at a suitable temperature, and mill the granules with an appropriate screen.
(v) Lubrication: prepared granules are lubricated using magnesium stearate.
Compression & coating: compress the lubricated blend using suitable punches and coat the core tablet using Opadry II white dispersion.
Example-2
Table-2
Sr. No. Ingredients Amount (% W/W)
Dry Mix
1 Bempedoic acid 50-54%
2 Sodium stearyl fumarate 10-12%
3 Microcrystalline cellulose 15-18%
4 Lactose monohydrate 07-09%
5 Sodium Starch Glycolate 10-12%
Binder
6 Co-povidone 2-4 %
7 Purified Water q.s
Pre-lubrication
8 Microcrystalline cellulose 15-18%
9 Sodium starch glycolate 10-12%
Lubrication
10 Magnesium Stearate 1-1.5 %
Core tablet weight --
Film Coating
11 Opadry II White 2.0-2.5%
12 Purified Water q.s.
Manufacturing procedure: Same as in Example 1
Example 3
Table-3
Sr. No. Ingredients Amount (% W/W)
Dry Mix
1 Bempedoic acid 45-60%
2 Sodium stearyl fumarate 0.1-3%
3 Microcrystalline cellulose 5-12%
4 Lactose monohydrate 5-12%
5 Sodium Starch Glycolate 2-6%
Binder
6 Co-povidone 1-4%
7 Purified Water @ q.s
Pre-lubrication
8 Microcrystalline cellulose 5-12%
9 Sodium starch glycolate 5-12%
Lubrication
10 Magnesium Stearate 0.2-4 %
Core tablet weight --
Film Coating
11 Opadry II White 1-4%
12 Purified Water q.s.
Manufacturing procedure: Same as in Example 1
Example-4
Table-4
Sr. No. Ingredients Amount
(Mg /Tab)
Ezetimibe Part (Part-1) Top Spray
1 Lactose Monohydrate 67.00
2 Sodium Starch Glycolate 6.00
3 Microcrystalline Cellulose 22.80
Binder Solution
4 Ezetimibe 10.00
5 Hypromellose 603 2.00
6 Sodium Lauryl Sulfate 2.20
7 Purified Water Qs
Total Weight 110.00
Bempedoic Acid Part (Part-2) RMG Granulation
1 Bempedoic Acid 180.00
2 Microcrystalline Cellulose 18.00
3 Sodium Stearyl Fumarate 2.50
4 Lactose Monohydrate 14.50
Binder Solution
5 Hypromellose 7.00
6 Purified Water Qs
Total weight 222.00
Part 3 (Tablet Compression & Film Coating)
1 Ezetimibe Granules 110.00
2 Bempedoic Acid Granules 222.00
3 Sodium Starch Glycolate 11.00
4 Lactose monohydrate 4.00
5 Microcrystalline Cellulose 12.00
6 Croscarmellose Sodium 4.00
7 Magnesium Stearate 4.00
Total weight 367.00
Film Coating
1 Opadry AMB Blue 9.00
2 Purified water Qs
Final Tablet Weight 376.00
Manufacturing procedure:
A. Bempedoic acid granules:
(i) Co-sift a bempedoic acid, microcrystalline cellulose, lactose monohydrate and sodium stearyl fumarate.
(ii) Load the bempedoic acid blend into a rapid mixer granulator.
(iii) Binder solution: hypromellose added into purified water with continuous stirring.
(iv) Granulating bempedoic acid blend using binder solution, dry the granules at a suitable temperature, and mill the granules with the appropriate screen.
B. Ezetimibe granules:
(i) Co-sift ezetimibe, lactose monohydrate, and microcrystalline cellulose in a fluid bed processor.
(ii) Binder solution: hypromellose dissolved in purified water.
(iii) Binder solution is used for granulating the ezetimibe blend using the top spray granulation method and drying the granules at a suitable temperature.
C. Milling and blending: dried granules of bempedoic acid and Ezetimibe and the addition of sodium starch glycolate, and lactose monohydrate, were milled.
D. Lubrication: prepared granules are lubricated using magnesium stearate.
E. Compression & coating: compress the lubricated blend using suitable punches and coat the core tablet using Opadry II blue dispersion.
Example-5
Table-5
Sr. No. Ingredients Amount
(%W/W)
Ezetimibe Part (Part-1) Top Spray
1 Lactose Monohydrate 20-24%
2 Sodium Starch Glycolate 3.5-4.5%
3 Microcrystalline Cellulose 10-15%
Binder Solution
4 Ezetimibe 2.5-3.0%
5 Hypromellose 1.5-2.5%
6 Sodium Lauryl Sulfate 0.1-0.7%
7 Purified Water --
Total Weight --
Bempedoic Acid Part (Part-2) RMG Granulation
1 Bempedoic Acid 44-55%
2 Microcrystalline Cellulose 10-15%
3 Sodium Stearyl Fumarate 0.1-0.7%
4 Lactose Monohydrate 20-24%
Binder Solution
5 Hypromellose 1.5-2.5%
6 Purified Water Qs
Total weight --
Part 3 (Tablet Compression & Film Coating)
1 Ezetimibe Granules ---
2 Bempedoic Acid Granules ---
3 Sodium Starch Glycolate 3.5-4.5%
4 Lactose monohydrate 20-24%
5 Microcrystalline Cellulose 10-15%
6 Croscarmellose Sodium 0.5-1.1%
7 Magnesium Stearate 0.5-1.1%
Total weight
Film Coating
1 Opadry AMB Blue 2.0-2.5%
2 Purified water q.s
Manufacturing procedure: Same as in Example 4
Example 6
Table-6
Sr. No. Ingredients Amount
(%W/W)
Ezetimibe Part (Part-1) Top Spray
1 Lactose Monohydrate 15-25%
2 Sodium Starch Glycolate 0.5-3%
3 Microcrystalline Cellulose 2-10%
Binder Solution
4 Ezetimibe 1-5%
5 Hypromellose 0.1-2%
6 Sodium Lauryl Sulfate 0.1-2%
7 Purified Water --
Total Weight --
Bempedoic Acid Part (Part-2) RMG Granulation
1 Bempedoic Acid 35-55%
2 Microcrystalline Cellulose 2-8%
3 Sodium Stearyl Fumarate 0.1-2%
4 Lactose Monohydrate 1-7%
Binder Solution
5 Hypromellose 0.5-3%
6 Purified Water QS
Total weight --
Part 3 (Tablet Compression & Film Coating)
1 Ezetimibe Granules ---
2 Bempedoic Acid Granules ---
3 Sodium Starch Glycolate 1-5%
4 Lactose monohydrate 0.5-4%
5 Microcrystalline Cellulose 1-5%
6 Croscarmellose Sodium 0.1-3%
7 Magnesium Stearate 0.1-3%
Total weight --
Film Coating
1 Opadry AMB Blue 1-5%
2 Purified water q.s
Manufacturing procedure: Same as in Example 4
Stability Study-Example 1
Table: 7
Batch No. BEM/FD000041/022
HDPE Bottle + 1g Silica gel
(30’s Count) HDPE Bottle + 1g Silica gel
(90’s Count) HDPE Bottle + 3g Silica gel
(500’s Count) Alu-Alu Blister
Pack
Condition 40°C/75%RH
Initial 1M 3M 6M 1M 3M 6M 3M 6M 1M 3M 6M
Assay (%) 99.1 99.6 100.3 99.5 101.0 98.8 100.0 100.1 99.7 99.9 99.2 99.5
Organic Impurities (%)
Bempedoic Acid Stage 1 ND ND ND ND ND ND ND ND ND ND ND ND
Any Individual Unspecified Degradation Product 0.040 0.038 Nil Nil 0.037 Nil Nil Nil Nil 0.044 Nil Nil
Total Impurities Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil
Dissolution (%)
20 mins 98.0 96.0 96.0 97.0 94.0 94.0 94.0 94.0 95.0 97.0 95.0 97.0
Water Content (% w/w) 2.28 1.86 1.90 2.02 2.12 2.14 2.12 2.22 2.14 2.36 2.53 1.97
ND: Not detected
All the impurity data at initial, 1 months, 3 Months and 6 months at 40°C /75% RH stability were found to be satisfactory.
Stability Study-Example 6
Table:8
Parameters 40°C/ 75% RH 25°C/ 60% RH
Initial 3M 6M 3M 6M
Assay 99.7 99.9 99.1 100 99.4
101.1 101.5 101 101.1 102.0
Water Content (w/w, By K.F. Titration) 2.4 1.9 1.7 1.9 1.8
Dissolution 88 96 89 95 90
97 100 95 101 96
Organic Impurities (w/w, by HPLC)
For Bempedoic Acid
1) Bempedoic Acid Stage -I ND ND ND ND ND
2) Any individual unspecified degradation product 0.02 0.02 0.02 0.01 0.02
3) Total degradation Products (Bempedoic Acid) 0.03 0.05 0.00 0.03 0.00
For Ezetimibe
1) Ezetimibe Tetrahydropyran analog BLOQ BLOQ BLOQ ND ND
2) Ezetimibe Ketone BLOQ 0.01 0.01 BLOQ BLOQ
3) Any individual unspecified degradation product 0.09 0.09 0.09 0.09 0.09
4) Total degradation Products (Ezetimibe) 0.18 0.20 0.20 0.19 0.2
Total degradation Products (Ezetimibe+ Bempedoic Acid) 0.2 0.3 0.3 0.2 0.2

ND: Not Detected; BLOQ: Below Limit of Quantification.
All the impurity data at initial, 3 Months and 6 months at 40°C /75% RH and 25°C/ 60% RH stability were found to be satisfactory.

Dated this the 13th day of June 2024

Mr. Thirupathi Bendram
AVP & Head - IPR
Alkem Laboratories Limited

,CLAIMS:We claim:
1. A stable pharmaceutical composition comprising: a) Bempedoic acid or its pharmaceutically acceptable salt thereof; b) one or more binder; c) pharmaceutically acceptable excipients; and optionally comprising Ezetimibe or its pharmaceutically acceptable salt thereof.

2. A stable composition as claimed in claim 1, wherein the composition is free of glidant.

3. The stable composition as claimed in claim 1, wherein the composition is prepared using wet granulation, dry granulation or direct compression method.

4. A stable pharmaceutical composition comprising: a) about 54% w/w of bempedoic acid or a pharmaceutically acceptable salt thereof, b) about 1% w/w of sodium stearyl fumarate, c) about 18% w/w of microcrystalline cellulose, d) about 9% w/w of lactose monohydrate, e) about 11.5% w/w of sodium starch glycolate, f) about 3% w/w of co-povidone, g) about 1.3% w/w of magnesium stearate, h) about 2.7% w/w of opadry white film coating based on total weight of the composition; and wherein the pharmaceutical composition is free of glidant.

5. A stable pharmaceutical composition comprising: a) about 45-60% w/w of bempedoic acid or a pharmaceutically acceptable salt thereof; b) about 10-25% w/w of microcrystalline cellulose; c) about 1-4% w/w of % Co-povidone, d) about 5-12% w/w of lactose monohydrate; e) about 5-12% w/w of sodium starch glycolate; f) about 0.2-4% w/w of magnesium stearate; g) about 0.1-3% w/w of sodium stearyl fumarate; h) about 1-4% w/w of Opadry II White; and wherein the pharmaceutical composition is free of glidant.

6. A stable pharmaceutical composition comprising: a) Ezetimibe part comprising about 2.7% w/w of ezetimibe, 18% w/w of lactose monohydrate, about 1.6% w/w of sodium starch glycolate, about 6.1% w/w of microcrystalline cellulose, about 0.6% w/w of hypromellose, about 0.6% w/w of sodium lauryl sulfate; b) Bempedoic acid part comprising about 48% w/w of bempedoic acid, about 5% w/w of microcrystalline cellulose, about 0.7% w/w of sodium stearyl fumarate, about 4% w/w of lactose monohydrate, 2% w/w of hypromellose; c) Extragranular part comprising about 3% w/w of sodium starch glycolate, about 1% w/w of lactose monohydrate, about 3.2% w/w of microcrystalline cellulose, about 1% w/w of croscarmellose sodium, about 1% w/w of magnesium stearate and film coating comprising about 2.4% w/w of opadry AMB blue based on total weight of the composition, wherein the pharmaceutical composition is free of glidant.

7. The stable composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 25°C/ 60% relative humidity and 40°C/ 75% relative humidity.

8. A stable pharmaceutical composition comprising: a) Ezetimibe part comprising about 1-5% w/w of ezetimibe, 15-25% w/w of lactose monohydrate, about 0.5-3% w/w of sodium starch glycolate, about 2-10% w/w of microcrystalline cellulose, about 0.1-2% w/w of hypromellose, about 0.1-2% w/w of sodium lauryl sulfate; b) Bempedoic acid part comprising about 35-55% w/w of bempedoic acid, about 2-8% w/w of microcrystalline cellulose, about 0.1-2% w/w of sodium stearyl fumarate, about 1-7% w/w of lactose monohydrate, 0.5-3% w/w of Hypromellose; c) Extragranular part comprising about 1-5% w/w of sodium starch glycolate, about 0.5-4% w/w of lactose monohydrate, about 1-5% w/w of microcrystalline cellulose, about 0.1-3% w/w of croscarmellose sodium, about 0.1-3% w/w of magnesium stearate and film coating comprising about 1-5% w/w of opadry AMB blue based on the total weight of the composition, wherein the pharmaceutical composition is free of glidant.

9. The pharmaceutical composition as claimed in claim 1, wherein the surfactant is sodium lauryl sulfate.

10. The pharmaceutical composition as claimed in claim 1, wherein the disintegrant is selected from sodium starch glycolate and croscarmellose sodium.